Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for multiple sclerosis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the development of a novel therapy that uses genetically modified cytolytic T lymphocytes (GM-CTL) to selectively eliminate ATL. The GM- CTL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-CTL. This receptor will consist of: a class II major histocompatibility complex (MHC) alpha and beta chains, b. covalently linked antigenic peptide, and c. the activation domain of the T cell receptor zeta chain. The ALT T-cell receptor will specifically interact with the NHC- peptide complex of the chimeric receptor. This interaction will activate the GM-cTL, which in turn will kill the ATL. By using GM-CTL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for multiple sclerosis and post-vaccination encephalomyelitis, experimental allergic encephalomyelitis (EAE). Chimeric construct design will be optimized using in vitro assays of GM-CTL activity. GM-CTL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of EAE. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM- CTL in treating autoimmune neurologic disease. It will establish a precedent for the analogous use of GM-CTL as a therapy for human autoimmune disease.